In contrast with the innumerable reports of enantioselective olefin and ketone hydrogenations in the literature, there are very few reports of homogenous hydrogenations of imides (Bruneau et al, Angew. Chem. Int. 2005, 44, 2021; Ikariya et al J. Am. Chem. Soc 2007, 129, 290; Ikariya et al, Angew. Chem. Int. 2009, 48, 1324). These literature hydrogenations of imides require extreme conditions (˜80° C., 30-60 atm H2) and also result in ring-opening of the imide by direduction (Scheme 1).

There appear to be no reports in the literature of the mono-reduction of an imide to the hydroxy lactam by homogeneous hydrogenation, notwithstanding an enantioselective version of this reaction. However, there are reports of enantioselective imide reductions using main-group hydride reducing agents that illustrate the potential of this hydrogenation (Asami et al. Chem. Lett. 1983, 385). In particular, LAH-type reagents have been utilized to carry out the desymmetrization of the cyclopropane-derived imide 1 in 83% ee. The hydroxy lactam was subsequently converted into (1R,3S)-cis-chrysanthemic acid (Scheme 2).

The desymmetrization of the imide 2 with various chiral LAH reagents in effort to prepare (˜)-Swainsonine (Scheme 3) has also been investigated (Chamberlin et al. J. Amer. Chem. Soc., 1990, 112, 8100).

As a final illustration, the desymmetrization of 3 with a reusable, polymer-bound chiral B—H reagent in 98% ee was also examined (Chen et al., Chem Pharm Bull 2005, 53, 743). The hydroxy lactam was subsequently converted into (+)-Biotin (Scheme 4).

Desymmetrization reactions that produce multiple stereogenic centers in a single enantioselective event are highly sought after in the academic and industrial synthetic communities. An extensive review of the desymmetrization of meso anhydrides and its use in the preparation of several classes of compounds was recently reported (Bolm, et al. Chem. Rev. 2007, 107:5683-5712).
Hydroxy lactams are useful building blocks for a variety of biologically significant molecules. They are particularly useful as precursors to iminium ions (Royer et al., Chem. Rev., 2004, 104, 2311-2352; Maryanoff et al., Chem. Rev. 2004, 104, 1431-1628; Speckamp et al., Tetrahedron, 2000, 56, 3817-3856; Pyne et al., Synthesis, 2009, 3, 339-368; Pyne et al., 2009, 4, 513-541).